PT  - JOURNAL ARTICLE
AU  - Dawson, John C.
AU  - Serrels, Bryan
AU  - Byron, Adam
AU  - Muir, Morwenna
AU  - Makda, Ashraff
AU  - García-Muñoz, Amaya
AU  - von Kriegsheim, Alex
AU  - Carragher, Neil O.
AU  - Frame, Margaret C.
TI  - A Synergistic Anti-Cancer FAK and HDAC Inhibitor Combination Discovered by a Novel Chemical-Genetic High-Content Phenotypic Screen
AID  - 10.1101/590802
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 590802
4099  - http://biorxiv.org/content/early/2019/03/27/590802.short
4100  - http://biorxiv.org/content/early/2019/03/27/590802.full
AB  - We mutated the Focal Adhesion Kinase (FAK) catalytic domain to inhibit binding of the chaperone, Cdc37 and ATP, mimicking the actions of a FAK kinase inhibitor. We re-expressed mutant and wild-type FAK in squamous cell carcinoma (SCC) cells from which endogenous FAK had been deleted, genetically fixing one axis of a FAK inhibitor combination high-content phenotypic screen to discover drugs that may synergize with FAK inhibitors. HDAC inhibitors represented the major class of compounds that potently induced multi-parametric phenotypic changes when FAK was rendered kinase-defective, or inhibited pharmacologically in SCC cells. Indeed, combined FAK and HDAC inhibitors arrest proliferation and induce apoptosis in a sub-set of cancer cell lines in vitro and efficiently inhibits tumor growth in vivo. Mechanistically, HDAC inhibitors potentiate inhibitor-induced FAK inactivation and reverses FAK-associated nuclear YAP in sensitive cancer cell lines. Here we report the discovery of a new clinically actionable synergistic combination between FAK and HDAC inhibitors.Significance We describe a chemical-genetic, high-content phenotypic screening approach to discover effective anti-cancer combinations of targeted therapeutics through which we identified a novel, synergistic and clinically actionable, combination of FAK and HDAC inhibitors.